Hot-Melt Extrusion with BASF Pharma Polymers Extrusion Compendium

Transcription

1 Hot-Melt Extrusion with BASF Pharma Polymers Extrusion Compendium K. Kolter, M. Karl, S. Nalawade, N. Rottmann Pharma Ingredients & Services. Welcome to more opportunities.

2 Hot-Melt Extrusion with BASF Pharma Polymers Extrusion Compendium K. Kolter, M. Karl, S. Nalawade, N. Rottmann BASF SE Pharma Ingredients & Services Ludwigshafen, Germany October 2010

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4 1 Introduction to Hot-Melt Extrusion for Pharmaceuticals 1 2 General Notes on BASF Pharma Polymers 2 3 Physico-chemical Characteristics Processability 3 4 Design of Extrusion Experiments 4 5 In-Vitro / In-Vivo Characteristics of HME Formulations 5 6 Manufacture of Final Dosage Forms 6 7 Flow Chart: From Screening to a Final Pharmaceutical Formulation 7 8 Practical Recommendations for Extrusion 8 9 Regulatory Aspects 9 10 Literature References Alphabetical Index 11

5 Contents 1 Introduction to Hot-Melt Extrusion for 8 Pharmaceuticals 2 General Notes on BASF Pharma Polymers Kollidon VA 64 / VA 64 Fine Soluplus Kollidon 12 PF, Kollidon 17 PF, Kollidon 30 and Kollidon 90 F Kollidon SR Kollicoat MAE 100P Kollicoat IR and Kollicoat Protect Lutrol F 127, Lµtrol micro 127 (Poloxamer 407) and Lutrol F 68, 31 Lµtrol micro 68 (Poloxamer 188) 2.8 Cremophor RH Polyethylene Glycols 33 3 Physico-chemical Characteristics 34 Processability 3.1 Glass Transition Temperature and Melting Temperature DSC-Analysis of Pure Polymers and Plasticizers / Solubilizers DSC-Analysis of Polymer-Plasticizer Mixtures DSC-Analysis of Polymer Mixtures Melt Viscosity Melt Viscosity of Pure Polymers Infl uence of Plasticizers on Melt Viscosity Decomposition by TGA TGA of Polymers TGA of Plasticizers TGA of Active Pharmaceutical Ingredients Specifi c Heat Capacity of Pure Polymers API Solubility Enhancement of Pure Polymers Calculation of Solubility Parameters of Pure Polymers, 53 Plasticizers and APIs 4 Design of Extrusion Experiments Extrusion of Pure Polymers Extrusion Temperature Range of Pure Polymers Appearance and Pelletizing Characteristics of Extrudates Dissolution Characteristics of Polymer Extrudates Decomposition of Polymers during Extrusion Extrusion of Polymer-Plasticizer Combinations Extrusion Temperature Range of Polymer-Plasticizer Combinations Appearance and Pelletizing Characteristics of 68 Polymer-Plasticizer Extrudates 4

6 4.2.3 Miscibility of Polymer-Plasticizer Combinations Extrusion of Polymer Mixtures Extrusion Temperature Range of Polymer Mixtures Appearance and Pelletizing Characteristics of Extrudates of 78 Polymer Mixtures 4.4 Solubilization Capacity of Active Ingredients in Polymers for 79 Hot-Melt Extrusion Film Casting Extrusion Results and Comparison 87 5 In-Vitro / In-Vivo Characteristics of 90 HME Formulations 5.1 In-Vitro Release Characteristics of HME Formulations In-Vivo Behavior of HME Formulations 92 6 Manufacture of Final Dosage Forms 94 7 Flow Chart: From Screening to a 95 Final Pharmaceutical Formulation 8 Practical Recommendations for Extrusion 96 9 Regulatory Aspects Literature References Alphabetical Index 108 5

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8 Acknowledgements First of all, we would like to thank our colleagues of the R&D Pharma Ingredient Group for their valuable contributions, in particular the members of the Extrusion Team Benjamin Strunk and Ronny Hoffmann. Our special thanks go to Dr. Angelika Maschke, Dr. Dejan Djuric, Dr. Thorsten Schmeller, Dr. Hendrik Hardung, Dr. Bettina Goldscheid and Timo Münch for their support, proofreading and constructive discussions. A special acknowledgement is due to Prof. Dr. Jörg Breitkreutz (Institute for Pharmaceutics and Biopharmaceutics, Heinrich-Heine-University, Duesseldorf, Germany) for his support and for providing the computer program SPWin (version 2.1) for the calculation of the solubility parameters. Finally, we wish to thank all other persons who were involved in the compilation of this extrusion compendium. 7

9 1 Introduction to Hot-Melt Extrusion for Pharmaceuticals In recent years, interest in hot-melt extrusion techniques for pharmaceutical applications has grown signifi cantly. Hot-melt extrusion (HME) is an established manufacturing process that has been used in the plastics and food industry since the 1930s. In the 1980s, BASF SE was the fi rst to apply the melt extrusion process based on polymers with a high glass transition temperature (such as polyvinylpyrrolidones) to pharmaceuticals [1]. Later on, Soliqs, the drug delivery business unit of Abbott GmbH & Co KG, commercialized the technology and subsequently launched several drugs [2]. A number of research groups have demonstrated HME processes as being viable techniques for the preparation of pharmaceutical drug delivery systems, including granules [3, 4], pellets [5, 6], sustained release tablets [7, 8, 9, 10, 11], transdermal and transmucosal drug delivery systems [12, 13, 14, 15, 16, 17, 18, 19, 20] and implants [21, 22, 23, 24]. The HME technique is an attractive alternative to traditional processing methods [25]. Examples for solving pharmaceutical challenges via HME are given in Table 1-1. Table 1-1 Advantages of hot-melt extrusion Problem Poor (low / unreliable) bioavailability due to poor API solubility Poor API stability during processing caused by hydrolysis Unreliable sustained release action Poor stability or tolerability of API in the stomach Poor taste of the API Manufacturing of fi lms Solution by HME Use of Hot-Melt Extrusion to prepare solid solution / dispersion or SEDDS (enhanced dissolution) Use of Hot-Melt Extrusion as alternative to wet agglomeration (no hydrolytic stress) Use of Hot-Melt Extrusion to prepare sustained release dosage form (single / multiple units) Use of Hot-Melt Extrusion to prepare enteric dosage forms (single / multiple units) Use of Hot-Melt Extrusion to prepare taste-masked dosage forms Use of Hot-Melt Extrusion to prepare oral strips or dermal patches Hot-melt extrusion is currently generating more and more interest as the percentage of poorly soluble new chemical entities in drug development is constantly increasing. For such molecules, hot-melt extrusion offers an opportunity to make them orally bioavailable [26]. Additional benefi ts are the creation of a reliable drug release profi le and a robust manufacturing process which can be run in practically any pharmaceutical factory. However, as with other breakthrough innovations, numerous obstacles had to be overcome before the technology and resulting dosage forms could be commercially exploited. Compared with other pharmaceutical technologies such as 8

10 tableting, hot-melt extrusion is still an emerging technology and its potential has not yet been fully explored. The technology itself can be defi ned as a process where a material which melts or softens under elevated temperatures and pressures is forced through an orifi ce by screws. A prerequisite of the polymer to be used in hot-melt extrusion is appropriate thermoplastic behavior; however, the number of such polymers approved for pharmaceutical use is limited. BASF offers a range of polymers with different structures and properties for use in hot-melt extrusion. 1 The extrusion process Extruders for pharmaceutical use have been designed and adapted for mixing drugs with carriers in various dosage forms. The signifi cant difference between extruders for thermoplastics and pharmaceutical applications is the equipment used and hence the contact surface, which must meet regulatory requirements. The contact parts of the extruders used in pharmaceuticals must not be reactive nor may they release components into the product. The extruder equipment is specially confi gured to fulfi ll all cleaning and validation standards applicable to the pharmaceutical industry. In principle, an extruder consists of barrels enclosing single or twin screws which transport and subsequently force the melt through a die, giving it a particular shape. The barrel can be heated to the desired temperature. Due to the external heat and shear provided by the screws, the polymer is plasticized and hence its viscosity reduced. Since the extruder is fed at one side and the extruded material exits from the other side, it is a typical continuous process; this makes it even more attractive for pharmaceuticals [27]. The hot-melt extrusion process comprises the steps melting, mixing and shaping (see Figure 1-1). The purpose of the feeding section is to transfer the materials from the feeder to the barrel. The polymer mixture typically begins to soften in the melting zone. The melt moves by circulation in a helical path by means of transverse fl ow, drag fl ow, pressure fl ow and leakages [25]. Thermoplastic polymers primarily exist in a molten state when entering the shaping section. The function of this zone is to reduce the pulsation fl ow and ensure a uniform delivery rate through the die. At the end of the barrels, the attached die dictates the shape of the extrudates. 9

11 Powder Die Tempering Cylinder Screw Extrudate Engine Shaping Mixing Melting Temperature: Residence time: above T g of polymer ( C) variable (0.5 5 min) Modifi ed according to: M. Thommes, Systematische Untersuchungen zur Eignung von kappa-carrageenan als Pelletierhilfsstoff in der Feuchtextrusion / Sphäronisation, Ph. D. Thesis, University of Düsseldorf, Figure 1-1 Principle of hot-melt extrusion The complete extrusion set-up consists of three distinct parts: A conveying and kneading system for material transport and mixing A die system for forming the extrudates Downstream auxiliary equipment (cooling, pelletizing and collecting) The components of the extruder are: The feed hopper (gravimetric or volumetric feeding) Temperature-controlled barrels (heating and / or cooling) Die (different die confi gurations are available) 10

12 Additional equipment: Process analytical technology (e.g. spectroscopic systems) Vacuum pumps for degassing extrudates Pelletizer equipment Calendering equipment In-process control parameters can be: Zone and die temperatures Screw speed Torque or power consumption Pressure Melt viscosity Feed rate 1 Extruders are available as single- or multi-screw versions. Twin-screw extruders utilize two screws usually arranged side by side. The use of two screws allows a number of different confi gurations to be obtained and imposes different conditions on all zones of the extruder. In the twin-screw extruder, the screws can either rotate in the same (co-rotating) or in the opposite (counter-rotating) direction [25]. Co-rotating extruders are the most important types for industrial applications. They can be operated at high screw speeds and high output and provide good mixing and conveying characteristics as well as more fl exibility in screw design. The co-rotating and counterrotating twin-screw extruders can be classifi ed as either non-intermeshing or intermeshing. In most cases, co-rotating intermeshing twin-screw extruders are used. The main advantages of single- and twin-screw extruders are listed below. Co-rotating High screw speed, high output More fl exibility in screw design Advantages of twin-screw compared to single-screw extruders [25]: Easier material feeding High kneading potential High dispersing capacities Less tendency to overheat (important for sensitive APIs) Shorter and constant residence times Figure 1-2 Counter-rotating Low screw speed, low output High shear forces High pressure between the screws Air entrapment Modifi ed according to: Thermo Fisher Scientifi c Inc. Twin-screw extruders 11

13 Advantages of single-screw compared to twin-screw extruders: Mechanical simplicity Low cost of investment The major advantages of the twin-screw extruders are in their conveying and transport mechanisms and in their mixing abilities compared to the single-screw extruders. This is why applications are continuing to expand within the pharmaceutical fi eld. Conveying and kneading elements Most extruders have a modular design to facilitate different screw confi gurations. The confi guration of the screw has a signifi cant impact on the extrusion process and can be designed to achieve either a high or a low shear. The length of the screws in the extrusion process is given in terms of L / D ratio (length of the screw divided by the screw diameter) [28, 29]. The confi guration of the screws can be varied by number and arrangement of conveying and kneading elements (see Figure 1-3) [26]. 12

14 Kneading elements Conveying element Conveying elements Profiles with open chambers: In the feeding sections For melt exchange For degassing (venting) Profiles with closed chambers: For high pressure build-up In front of kneading elements Kneading elements Kneading elements are used to introduce shear energy to the extruded materials. The elements are arranged in different offset angles (30, 60 and 90 ) used for: Plasticizing Mixing Dispersing Figure 1-3 Screw elements, their application and effects on the extrusion process 13

15 The design of the kneading elements has an infl uence on the mixing behavior within the extrusion process. The advance angle also determines the conveying ability of the element ranging from forwarding (30 and 60 ) and neutral (90 ) to reversing (30 reverse) character. Neutral elements (90 ) push material neither forwards nor backwards. Irrespective of the reverse-fl ighted element, ability for mixing and shearing of the material increases the higher the advance angle. Reverse-fl ighted kneading blocks have a retaining character and are usually utilized when substantial mechanical stress has to be exerted onto the material [4]. Feeding Powder or granules are usually gravimetrically dosed into the extruder. The material is heated and more or less melted in the fi rst part. Thereafter, the material is mixed and homogenized by the kneading elements, and, at the end, extruded through a die which can have various shapes. Residence times in the extruder vary depending on the size of the extruder, screw speed, screw confi guration and feed rate. They range typically from 0.5 to 5 minutes. The feeding mode of the feeders can be gravimetric and volumetric. Gravimetric feeding is typically specifi ed for c-gmp installations. Feeders for pharmaceutical materials have the following characteristics: They are easy to clean and disassemble Stainless steel components are used Stainless steel shrouding is used for non-stainless-steel parts Qualifi cation documentation is available Table 1-2 Feeder and feeding modes Gravimetric feeding Screw rotation speed is adjusted to keep the mass-fl ow rate constant (quantity per unit of time) Gravimetric feeding is typically specifi ed for GMP installations Volumetric feeding Used as refi ll devices for gravimetric feeders High fl uctuation in the mass-fl ow rate for metering dry ingredients into the extruder (variations in material bulk density because of handling / variations in screw fl ight loading) 14

16 Downstream processing Downstream extrusion equipment is used to fi nish, shape and analyze the extruded product. After leaving the die in the form of continuous strands or ribbons, cooling and cutting is performed, resulting in the required particle size. Process Analytical Technology (PAT) instruments such as in-line NIR (Near Infrared Spectroscopy) can be used to check the homogeneity of the active ingredient in the extrudate. 1 Examples of downstream systems are: Cooling of the extrudates with air or nitrogen on stainless steel conveyors or PTFE or in a non-solvent medium Shaping devices (calender, pelletizing device, Figure 1-4) Film and lamination systems for transmucosal/transdermal applications Cyclic molding Chill rolls and torque winders for cooling and collecting the extrudates Figure 1-4 Pelletizer 15

17 Process variables of twin-screw extrusion Process variables in twin-screw extrusion can be divided into step and continuous changes. Continuous changes include modifi cations during the running process and step changes require off-line modifi - cations (Table 1-3). Table 1-3 Variables in twin-screw extrusion Step changes: Screw design Die design Barrel layout Continuous changes: Screw speed Feed rate Barrel temperature Screw speed, feed rate and barrel temperature are the most relevant process parameters in twin-screw extrusion. These parameters particularly infl uence the system parameters mechanical energy, residence time and the temperature of the material. The correlation of the feed rate and screw speed on the residence time of Kollidon VA 64 in a 16 mm twin-screw extruder (length to diameter ratio of 40) at 170 C is illustrated in Figure 1-5. The residence time was determined by measuring the time for conveying a colored additive such as Kollicoat IR Red and Kollicoat IR Brilliant Blue from the feeding section to the die exit. 300 Residence time [s] RPM 200 RPM 300 RPM 400 RPM 500 RPM Feed rate [g/h] Figure 1-5 Example of residence time in a 16 mm twin-screw extruder 16

18 On increasing feed rate and screw speed, the residence time of the material decreased and the torque of the machine increased. At higher temperatures, the torque decreased due to a lowering of the melt viscosity of the polymer (Figure 1-6). 1 Residence time Torque Feed rate [kg/h] Screw speed [rpm] Temperature [ C] Figure 1-6 Effect of feed rate, screw speed and temperature on HME Drug delivery systems Hot-melt extrusion is mainly used to formulate poorly soluble actives as solid dispersions [30, 31]. Of the various types of solid dispersions, 3 are relevant for pharmaceutical applications since the applied polymers are usually amorphous. Principally, the drug can be either dissolved or dispersed whilst in an amorphous or crystalline state. A thermodynamically stable formulation (Figure 1-7) is achieved when the drug is completely dissolved below its saturation solubility in the polymer, resulting in a solid solution. When the drug concentration exceeds the saturation solubility, the whole system is only kinetically controlled since the drug may crystallize or precipitate out of the polymer during storage. Formulation in the middle is also kinetically controlled. This is because the amorphous drug is dispersed in an amorphous polymer and as the drug may crystallize, defi nitely changing the dissolution and biopharmaceutical properties. The system on the left is quite stable in this case the polymer contains crystalline drug because only Ostwald ripening can occur, leading to larger crystals. However, this is not very pronounced due to the low diffusivity of the drug in a solid polymer. 17

19 Drug Crystalline Amorphous Molecularly dissolved Polymer Amorphous Amorphous Amorphous Thermodynamic stability Almost stable Unstable (kinetically controlled) Stable (drug below saturation solubility) Figure 1-7 Relevant types of solid dispersions Based on the ph-dependant solubility of the polymer, instant-release (IR), enteric or sustained-release (SR) drug delivery systems can be developed. The selection of the polymer strongly determines the release rate of the drug (Figure 1-8). In most cases, instant-release systems have been developed and commercialized so far. IR Kollidon VA 64 Soluplus Kollidon grades Kollicoat IR Kollicoat Protect Lutrol F grades Enteric Kollicoat MAE 100P SR Kollidon SR Figure 1-8 Application fields of BASF pharma polymers 18

20 Polymers for hot-melt extrusion The polymer must exhibit thermoplastic characteristics in order to enable the hotmelt extrusion process and it must be thermally stable at the extrusion temperatures employed. Other relevant characteristics are: suitable T g or T m ( C), low hygroscopicity and no toxicity since larger amounts of polymer are used (Figure 1-9). Polymers with a high solubilization capacity are particularly suitable because large quantities of drugs can be dissolved. Some features like lipophilicity, hydrogen bonding acceptors or donors [32] and amide groups are basic prerequisites for a high solubilization capacity; the same applies to organic solvents (Figure 1-10). This explains why povidone, copovidone and Soluplus are highly suitable for hot-melt extrusion. Copovidone and Soluplus in particular are much more lipophilic than many other water-soluble polymers containing hydroxyl groups and, therefore, is best suited to the lipophilicity of poorly soluble drugs. In addition, the solubility parameter can be used to determine whether actives and polymers are compatible [33, 34]. 1 Thermoplastic behavior deformability is essential Suitable T g C High thermal stability C Low hygroscopicity prevents crystallization No toxicity application of large amounts High or no solubilization thermodynamically stable capability formulation Figure 1-9 Basic requirements for polymers used in HME 19

21 Impact on solubilization capability Lipophilicity Solubility parameter Hydrogen bonding Amide structures acting as hydrogen bond acceptors Excellent solvents Dimethyl acetamide Dimethyl formamide Pyrrolidone Methyl pyrrolidone Poor solvents Methanol Acetone N C C O C OH O Similia similibus solvuntur Excellent polymers Soluplus Kollidon VA 64 Kollidon 30 Poor polymers Kollicoat IR HPC Figure 1-10 Solubilization capability When the drug is incorporated in a supersaturated form, the whole mixture should have a very rigid structure in order to minimize crystallization either from dissolved drug or from amorphous drug particles [35]. The formulation, being a solid solution, dissolves in gastric or intestinal fl uids forming a supersaturated solution of the drug in these aqueous media, thus enhancing dissolution and bioavailability [36]. Extrudability is mainly determined by the glass transition or melting temperature and melt viscosity [37]. Materials of high molecular weight generate a high melt viscosity and are diffi cult to extrude. A high glass transition or melting temperature requires high processing temperatures, which can degrade sensitive drugs. As a general rule, extrusion processes can be run at temperatures C above glass transition temperature. Most polymers demonstrate thixotropic behavior, which means that the viscosity reduces as a function of increasing shear stress. Plasticizers added to the polymer can reduce glass transition temperature and melt viscosity, thus facilitating the extrusion process [38]. Some actives may also have a plasticizing effect. An extrusion temperature range of C for a drug containing polymer seems to be best, since the drug should survive thermal stress lasting for minutes in a non-aqueous environment. 20

22 In extruded drug delivery systems, the polymer serves as a matrix and, in consequence, larger quantities are required than in its more common use as a binder or coating agent. It is crucial that the polymers are non-toxic and approved in various countries at high doses. Kollidon VA 64 completely fulfi lls this requirement. Based on toxicological studies, other polymers may also be used in high doses; however, these have not yet been approved in such doses. The regulatory status of the BASF pharma polymers is summarized in chapter 9 of this compendium. 1 Advantages of hot-melt extrusion in detail Within the pharmaceutical industry hot-melt extrusion has been used for various purposes, such as: Enhancement of the dissolution rate and bioavailability of a drug Controlling or modifying drug release Taste masking Stabilizing the API Parenteral depots and topical delivery systems Increasing dissolution rate and bioavailability of APIs that are poorly soluble in water are important challenges in dosage form development (Figures 1-11 and 1-12). One approach is the formation of a solid solution /dispersion of a drug with hydrophilic excipients. The solid solution is the ideal type for increasing drug release. In this formulation, the drug is molecularly dissolved and has a lower thermodynamic barrier for dissolution [39]. Crystalline drug Hot-melt extrusion Solid solution extrudate Tablets + Temp. + Polymer Polymer matrix acts as a solid solvent for drug molecules In the ideal case, the drug is molecularly dissolved in the polymer Enhanced rate of dissolution and solubility of drug molecules compared to the crystalline form Figure 1-11 From poor API solubility to a final formulation 21

23 Powder mixing Melt extrusion Spheronisation Pelletizing / milling Direct shaping (Calendering) Tableting or capsule filling Tableting or capsule filling Figure 1-12 Hot-melt extrusion for pharmaceutical dosage forms Once developed, hot-melt extrusion is a reliable and robust process offering benefi ts in cost-effi ciency. Compared to other processes for the production of solid solutions, it is far less complex, since the manufacturing of such dosage forms requires only a few steps and avoids the use of organic solvents. Hot-melt extrusion also has advantages over solvent-based methods of forming solid solution /dispersions: No need to handle explosive solvents Absence of residual solvents Continuous processing possible Possibility of continuous processing Fewer process steps High product density Non-dusty pellets (e.g. for HAPI formulations) Small-scale equipment Non-aqueous process Besides oral drug formulations, the hot-melt extrusion technique can be employed to manufacture parenteral depots such as injectible implants and stents and topical delivery systems such as dermal or transdermal patches. For these applications, the extrusion process is often combined with a shaping step or injection molding. 22

24 Injection molding combined with hot-melt extrusion Extrusion is a process for producing materials with defi ned physical and mechanical properties, while injection molding is a suitable process for shaping and sizing these materials to different forms for fi nal applications. Injection molding has traditionally been used for producing parts with different sizes and different shapes from both thermoplastic and thermosetting materials. In this process, materials in the form of powder or granules are fed into a heated barrel. The barrel contains a screw which can convey and mix (the degree of mixing is not comparable to extrusion) the materials. The barrel is heated externally and the heat is transferred from the barrel to the screw and hence to the materials. Due to the reciprocating action of the screw, the melt is forced by pressure into a mold cavity attached to the end of the screw. The melt cools down in the mold and acquires a defi ned shape. After solidifi cation, product is released by opening the mold. Molds are generally made of steel or aluminum. The process looks simple in terms of its principle, but is complex in terms of process parameters. 1 The injection molding process is generally influenced by the following parameters: Material type (crystalline, semi-crystalline or amorphous) Screw (also barrel) material and its design Mold material and its design Physical properties of the melt and its solid form Cycle time Although injection molding was already introduced by Speiser in 1964 as a pharmaceutical technology to produce sustained-release dosage forms [40], its use within the pharmaceutical industry has been limited to date to a few specifi c applications. A study of the literature shows that some groups have been actively involved in utilizing the potential of injection molding for pharmaceutical applications and medical devices. One of the studies includes the development of polyethylene [41] and polyethylene glycol matrices [42] and the use of soy protein in injection [43] and coinjection-molded [44] matrices. Eith et al. evaluated the development of an injectionmolded starch capsule [45]. Egalet, a novel drug delivery system prepared using injection molding, consists of an impermeable shell of cetostearyl alcohol and ethyl cellulose enclosing a matrix plug composed of drug, polyethylene glycol monostearate and polyethylene oxide, drug release being controlled by modulating the erosion of the matrix [46]. Recently, in order to produce sustained-release matrix tablets, hotmelt extrudates of ethyl cellulose as a release-controlling polymer and hydroxypropyl methylcellulose as a hydrophilic drug release modifi er together with different drugs such as ibuprofen and metoprolol tartrate were molded into tablets using a lab-scale injection molder operating at the same temperature as the extruder [47, 48]. Apart from tablet applications, considering the broad window of injection molding for different thermoplastics and biodegradable polymers, pharmaceutical polymers can be molded into fi lms, rods, rings and shaped implants. 23

25 2 General Notes on BASF Pharma Polymers BASF SE offers a variety of polymers based on different monomers and chemical structures which can be employed in hot-melt extrusion applications. The portfolio comprises homopolymers, copolymers, amphiphilic copolymers as well as solubilizers and plasticizers, which are described in this chapter in more detail [49, 50, 51]. Solutol HS 15 and Cremophor EL can also be used in hot-melt extrusion but are not described here in detail. Table 2-1 List of BASF pharmaceutical excipients suitable for hot-melt extrusion and their pharmacopoeial monographs Exipient Ph. Eur. Monograph USP-NF Monograph Kollidon VA 64 Copovidone Copovidone Soluplus - - Kollidon 12 PF Povidone (K-value 12) Povidone (K-value 12) Kollidon 17 PF Povidone (K-value 17) Povidone (K-value 17) Kollidon 30 Povidone (K-value 30) Povidone (K-value 30) Kollidon 90 F Povidone (K-value 90) Povidone (K-value 90) Kollidon SR - - Kollicoat MAE 100P Methacrylic acid ethacrylate copolymer 1:1 Kollicoat IR Macrogol polyvinyl alcohol grafted copolymer Kollicoat Protect Macrogol polyvinyl alcohol grafted copolymer + poly(vinyl alcohol) Lutrol F 127 / Lµtrol micro 127 Lutrol F 68 / Lµtrol micro 68 Methacrylic acid copolymer type C Ethylene glycol and vinyl alcohol graft copolymer Ethylene glycol and vinyl alcohol graft copolymer + polyvinyl alcohol Poloxamer 407 Poloxamer 407 Poloxamer 188 Poloxamer 188 Lutrol E grades Macrogols Polyethylene glycols Cremophor RH 40 Macrogolglycerol hydroxystearate Polyoxyl hydrogenated 40 castor oil 24

26 2.1 Kollidon VA 64 / VA 64 Fine The Kollidon VA 64 grades are manufactured by free-radical polymerization of 6 parts of N-vinylpyrrolidone and 4 parts of vinyl acetate. Vinylpyrrolidone is a hydrophilic, water-soluble monomer whereas vinyl acetate is lipophilic and water-insoluble. The ratio of both monomers is balanced in such a way that the polymer is still freely water soluble. 2 Properties Vinylpyrrolidone / vinyl acetate 60 / 40 Appearance White or slightly yellowish free fl owing powder Molecular weight ~ g / mol K-value (1 % in water) Solubility CH N CH 2 CH CH 2 O O O C Solutions of up to 50 % can be prepared: water, ethanol, isopropanol, methanol, DMF, methanol / acetone (1:1, w / w %), ethanol / acetone (1:1, w / w %) Solutions of up to 25 % can be prepared: acetone Solutions of > 10 % can be prepared: methylene chloride, glycerol, propylene glycol Less soluble in: ether, cyclic, aliphatic and alicyclic hydrocarbons n CH 3 m Figure Properties and structural formula of Kollidon VA 64 Pharmaceutical applications in addition to HME: Kollidon VA 64 is used in the pharmaceutical industry as a binder in the production of granules and tablets by wet granulation, as a dry binder in direct compression, as an additional fi lm former in coatings on tablets, as a protective layer and sub-coat for tablet cores and as a fi lm-forming agent in sprays. Intended release profile of extrudates: Since Kollidon VA 64 is quite soluble in aqueous media, the release profi le of these formulations is mostly instant release; however, it can also be used in modifi ed release drug delivery systems. 25

27 2.2 Soluplus Soluplus is a polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer. It has an amphiphilic structure and can be regarded as a polymeric solubilizer. This innovative excipient was launched in 2009 and was designed to be used in hotmelt extrusion and to solubilize poorly soluble actives. Properties PEG 6000 / vinylcaprolactam / vinyl acetate 13 / 57 / 30 Appearance White to yellowish free fl owing granules Molecular weight ~ g / mol K-value (1 % in ethanol) Solubility Soluble in water and many organic solvents (see Figure 2.2.2) HO O O O O n m O N l O Figure Properties and structural formula of Soluplus HO Concentration of Soluplus [%] Acetone Ethanol DMF Methanol MeOH/ Acetone (1:1 w/w%) EtOH/ Acetone (1:1 w/w%) Figure Solubility of Soluplus in organic solvents 26

28 Pharmaceutical applications in addition to HME: Soluplus acts as a matrix polymer for solid solutions prepared for instance by spray drying or evaporation techniques. It can also be used as a wet or dry binder, fi lm former in oral strips, solubilizer, emulsion stabilizer and protective colloid. In most of those applications it improves the formulation characteristics by its outstanding solubilizing effect. Furthermore, Soluplus can increase the bioavailability of poorly soluble drugs. 2 Intended release profile of extrudates: Soluplus is expected to show an instant release profi le. 2.3 Kollidon 12 PF, Kollidon 17 PF, Kollidon 30 and Kollidon 90 F The soluble Kollidon grades are obtained by free-radical polymerization of vinylpyrrolidone. The current range of soluble Kollidon grades consists of pharmaceutical grade products with different nominal K-values. Table Molecular weight (M W ) values and K-values for different grades of Kollidon Kollidon grade M W [g / mol] K-value (1 or 5 % solutions in water) Kollidon 12 PF ~ Kollidon 17 PF ~ Kollidon 30 ~ Kollidon 90 F ~ Properties Polyvinylpyrrolidone Appearance Almost white free fl owing powder Solubility Solutions of > 10 % can be prepared: water, methanol, isopropanol, chloroform, n-butanol, cyclohexanol, n-propanol, ethanol, polyethylene glycol 400, glycerine, propylene glycol, methylene chloride, triethanolamine Less soluble (< 1 %) in: cyclohexane, pentane, diethyl ether, carbon tetrachloride, ethyl acetate, toluene, liquid paraffi n, xylene N O n Figure Properties and structural formula of polyvinylpyrrolidone (povidone) 27

29 Pharmaceutical applications in addition to HME: The general properties of the soluble Kollidon grades in pharmaceuticals are solubility in all conventional solvents, adhesive and binding power, fi lm formation, affi nity to hydrophilic and hydrophobic surfaces, ability to form water-soluble complexes and thickening properties. Intended release profile of extrudates: All PVP powders are quite water-soluble and therefore intended to be used for instant release dosage forms. 2.4 Kollidon SR Kollidon SR is a spray-formulated mixture of polyvinyl acetate and polyvinylpyrrolidone (povidone) in the ratio 8:2. Properties Polyvinyl acetate / polyvinylpyrrolidone 80 / 20 Appearance White or slightly yellowish, free fl owing powder Molecular weight Polyvinyl acetate: ~ g / mol Povidone: ~ g / mol K-value (1% in tetrahydrofuran) Solubility Soluble in N-methylpyrrolidone, acetone, methanol Insoluble in water, ethanol, isopropanol CH O CH 2 O C CH 3 n CH N CH 2 O m Figure Properties and structural formula of Kollidon SR Pharmaceutical applications in addition to HME: Kollidon SR can be used for the production of sustained release matrix preparations in the form of tablets, pellets and granules. The recommended technology for the production of sustained release matrix tablets based on Kollidon SR is direct compression, but also roller compaction and wet granulation can be used. Intended release profile of extrudates: Kollidon SR is insoluble in water and is expected to deliver the active in a sustained release manner [52, 53]. 28

30 2.5 Kollicoat MAE 100P This copolymer consists of methacrylic acid and ethyl acrylate in a ratio of 1:1. It is an anionic copolymer that can be neutralised by bases such as sodium hydroxide. 2 Properties Methacrylic acid / ethyl acrylate 50 / 50 Appearance White redispersible powder with a faint characteristic odor Molecular weight ~ g / mol Solubility Dissolves in slightly alkaline, aqueous media; readily soluble in ethanol, methanol CH 2 CH 3 C COOH n CH 2 CH COOC 2 H 5 m Figure Properties and structural formula of Kollicoat MAE 100P Pharmaceutical applications in addition to HME: The main application of Kollicoat MAE 100P is as a fi lm former in enteric coatings for solid dosage forms such as enteric tablets and pellets. Intended release profile of extrudates: Kollicoat MAE 100P is intended to be used as an enteric matrix in hot-melt extrusion formulations, the drug being released mainly in the intestine. 2.6 Kollicoat IR and Kollicoat Protect Kollicoat IR powder (Polyvinyl alcohol polyethylene glycol graft copolymer) comprises polyethylene glycol and polyvinyl alcohol in the ratio of 25:75 (w / w %). The polyethylene glycol chain forms a backbone onto which side chains of polyvinyl alcohol are grafted. Kollicoat Protect is a formulated mixture of Kollicoat IR and polyvinyl alcohol. 29

31 Properties Polyvinyl alcohol / polyethylene glycol 75 / 25 Appearance White to faintly yellow free fl owing powder Molecular weight ~ g / mol Solubility Water, weak acid / weak bases (up to 40 %) Ethanol + water (1:1) (up to 25 %) Practically insoluble in 96 % ethanol and non-polar solvents CH 2 O CH 2 CH 2 O CH 2 CH 2 O O CH CH 2 O CH 2 CH O CH 2 CH 2 CH CH 2 CH OH OH CH 2 CH CH 2 CH OH OH Figure Properties and structural formula of Kollicoat IR Properties Kollicoat IR / polyvinyl alcohol 60 / 40 Appearance White to off-white free fl owing powder Molecular weight ~ g / mol Figure Properties of Kollicoat Protect Pharmaceutical applications in addition to HME: Kollicoat IR acts as a fl exible fi lm forming agent in instant release coatings, as a water-soluble binding agent in wet granulation, as a pore-forming agent for adjusting release rates, as a fi lm former in oral strips, as a protective colloid and as a stabilizer of emulsions and suspensions. Kollicoat IR combines enormous fl exibility with extremely low viscosity in water. Kollicoat Protect can be used as a protective fi lm against oxidation and hydrolysis of the active ingredient. It can be used to mask taste, to facilitate the swallowing of tablets, to improve their appearance or as a sub-coating. Kollicoat Protect possesses all the advantages of Kollicoat IR, e.g. rapid dissolution in water, a high degree of adhesion, also on lipophilic surfaces, enormous fl exibility and low viscosity in water. 30

32 Intended release profile of extrudates: Due to the good water solubility of Kollicoat IR and Kollicoat Protect, an instant release profi le can be expected [54]. 2.7 Lutrol F 127, Lµtrol micro 127 (Poloxamer 407) and Lutrol F 68, Lµtrol micro 68 (Poloxamer 188) 2 The Lutrol F grades F 68 / F 127 and Lµtrol micro 68 / micro 127 are synthetic copolymers of ethylene oxide (a) and propylene oxide (b) where a = approx. 80 and b = approx. 27 for Lutrol F 68 / Lµtrol micro 68 and a = approx. 101 and b = approx. 56 for Lutrol F 127 / Lµtrol micro 127. Principally, the Lutrol grades are amphiphilic molecules where polyoxypropylene represents the lipophilic and polyethylene glycol the hydrophilic part. Typically, Lutrol F gels show increased viscosities when the temperature increases from room temperature to 40 C. Properties Ethylene oxide / propylene oxide Different ratios Appearance Lutrol F 68 / F 127 White, coarse-grained powders with a waxy consistency Molecular weight Lutrol F 68 / micro 68: ~ 8500 g / mol Lutrol F 127 / micro 127: ~ g / mol Solubility Lutrol F 127 / micro 127 is soluble in water and blends of alcohol and water, but is insoluble in diethyl ether, paraffi n wax and fatty oils Lutrol F 68 / micro 68 is freely soluble in water (opalescent solution) and ethanol, but is insoluble in diethyl ether, paraffi n and fatty oils Appearance Lµtrol micro 68 / 127 White microprilled powders with a weak odor Lutrol F 68 / micro 68: Methylene chloride approx. 35 % Chloroform approx. 40 % Acetonitrile approx. 20 % Acetone approx. 2 % Ethyl acetate approx. 1.5 % CH 3 HO CH 2 CH 2 O CH CH a 2 CH O 2 CH 2 O H b a Figure Properties and structural formula of Lutrol F 68 / micro 68 and Lutrol F 127 / micro

33 Pharmaceutical applications in addition to HME: Lutrol F 68 is employed as an emulsifi er and solubilizer, also in drug formulations for parenteral use. Furthermore, it is used as a dispersing and wetting agent, to prepare solid dispersions and to improve the solubility, absorption and bioavailability of poorly soluble actives in solid oral dosage forms. The formulations are usually processed by melt granulation and spray granulation. Lutrol F 127 is used primarily as a thickening agent and gel former, but also as a co-emulsifi er and consistency enhancer in creams and liquid emulsions. It is also used as a solubilizer for certain active substances in pharmaceutical and cosmetic formulations. Lµtrol micro 68 and Lµtrol micro 127 are poloxamers designed for direct compression, roller compaction, wet or melt granulation and hot-melt extrusion. This is because they have a much smaller particle size (approx. 50 µm) than the prilled grades, which renders them compatible with the particle sizes of actives and other excipients. Thus, these fi ne grades can be blended with drug mixtures without segregation, which is usually a risk when using the prilled Lutrol grades. Their functionality is mainly for improving the wetting and dissolution of poorly soluble drugs. In addition they can also act as water-soluble lubricants in tablet formulation. Intended use in HME: Poloxamers are intended to be used as plasticizers and as wetting and dissolution enhancers. Lµtrol micro grades can be preblended with other components and also mix more homogeneously in the extruder. 2.8 Cremophor RH 40 Cremophor RH 40 (macrogolglycerol hydroxystearate 40) is a non-ionic solubilizer and emulsifying agent. Properties Cremophor RH 40 consists of Hydrophobic part: glycerol polyethylene glycol hydroxystearate, together with fatty acid glycerol polyglycol esters; Hydrophilic part: polyethylene glycols and glycerol ethoxylate Appearance White to yellowish paste at 20 C Solubility Soluble in water, ethanol, 2-propanol, n-propanol, ethyl acetate, chloroform, carbon tetrachloride, toluene, xylene Figure Properties of Cremophor RH 40 32

34 Pharmaceutical applications in addition to HME: The main application is as a solubilizer and emulsifi er in oral and topical liquid and semi-solid dosage forms. 2.9 Polyethylene Glycols Polyethylene glycols (PEGs) are liquids or low-melting solids depending on their molecular weights. They are prepared by the polymerization of ethylene oxide and are commercially available with a wide range of molecular weights. The numbers that are often included in the names of PEGs indicate their average molecular weights, e.g. a PEG with n=9 would have an average molecular weight of approximately 400 g /mol and would be labeled PEG 400 (Lutrol E 400). Intended use in HME: Cremophor RH 40 is intended to be used as plasticizer or solubility enhancer for actives that are poorly soluble in water. Properties Polyethylene glycols Appearance Liquids or low-melting solids Molecular weight ~ 300 to ~ g / mol Solubility Polyethylene glycols are readily soluble in water, ethanol, acetone, glycols and chloroform H Figure O O n H Properties and structural formula of PEG 2 Pharmaceutical applications in addition to HME: PEGs of different molecular weights are used as co-solvents, plasticizers, thickening agents and as matrix formers in oral, dermal and parenteral dosage forms. Intended use in HME: The various PEGs are intended to be used as plasticizers. 33

35 3 Physico-chemical Characteristics Processability Polymers for hot-melt extrusion must exhibit thermoplastic characteristics in order to make the hot-melt extrusion process possible and they must be thermally stable at the extrusion temperatures employed. Other relevant characteristics are: suitable glass transition and melting temperature (T g or T m ) of C, low hygroscopicity and no toxicity since larger amounts of polymer are used [26]. The extrudability of a polymer is mainly determined by T g or T m and melt viscosity [37]. Polymers with a high molecular weight exhibit high melt viscosity and are diffi cult to extrude. Moreover, a high T g or T m requires a high processing temperature which can cause degradation of sensitive actives [55]. As a general rule, an extrusion process should be run at temperatures C above the T g. Most polymers demonstrate thixotropic behavior, which means that the viscosity reduces as a function of increasing shear stress. 3.1 Glass Transition Temperature and Melting Temperature To determine the glass transition temperature and the melting points of the polymers, DSC-analysis was performed. These values should prove helpful in determining the lowest process temperatures to be used for the polymers in hot-melt extrusion. Experimental method: Differential Scanning Calorimetry (DSC): DSC studies were performed using a Q2000 (TA Instrument, USA). DSC scans were recorded at a heating rate of 20 K / min in the second heating run. Additional experimental parameters for measurements of pure polymers, plasticizers and polymer-plasticizer mixtures: All measurements were performed in a 2 bar pressurized pan except for Cremophor RH 40 and Lutrol F 127, which were tested in an open pan. The drying conditions of polymers and plasticizers had to be adjusted for every single sample to ensure complete drying (drying above the T g ) without decomposition. The vacuum drying temperature varied from 140 C to 200 C. Additional experimental parameters for measurements of polymer mixtures: The polymer blends were predried in open pans inside the DSC apparatus for ten minutes. The drying temperature varied from 160 C to 200 C DSC-Analysis of Pure Polymers and Plasticizers / Solubilizers The glass transition temperature of PVP homopolymers increases from 90 C to 156 C as a function of molecular weight. The relatively low glass transition temperature of 34

36 Kollidon VA 64 is caused by the soft monomer vinyl acetate and in addition to that in the case of Soluplus by the covalently bound PEG moiety. Soluplus can be regarded as an internally plasticized molecule. The PEGs and poloxamers exhibit glass transition temperatures below freezing point; thus only the melting point is given here. T g /T m [ C] T g [ C] T m [ C] 55 3 Kollidon VA 64 Soluplus Kollidon 12 PF Kollidon 17 PF Kollidon 30 Kollidon 90 F Kollidon SR Kollicoat MAE 100P Kollicoat IR Kollicoat Protect Lutrol F 127 PEG 1500 Lutrol F 68 Figure Glass transition temperatures and melting points of all tested BASF pharma polymers and plasticizers DSC-Analysis of Polymer-Plasticizer Mixtures DSC is also an excellent tool for studying the impact of plasticizers in polymers on glass transition temperature. For this reason, extrudates and cast fi lms consisting of polymer and plasticizer were analysed concerning their T g. Experimental methods: 1. Polymer-plasticizer extrudates (Extrusion): The hot-melt extrusion of the polymerplasticizer mixtures was performed using a twin-screw extruder ZSK 25 (Coperion Werner & Pfl eiderer, Germany) with a screw diameter of 25 mm and a length to diameter ratio of 34. Several extrusion parameters were varied: Loading of the extruder from 2.5 to 5 kg / h, extrusion temperature of C and the speed of the extruder screws from 100 to 150 rpm. The screw confi guration for all experiments was kept constant. After extrusion, the samples were cooled down on a conveyor belt and subsequently granulated. 2. Polymer-plasticizer films (Film Casting): Polymer and plasticizer were dissolved in water and the solution casted using a Coatmaster (Erichsen Testing Equipment, Germany) using knives with different die gaps ( m) and then dried at 40 C. 35

37 Pure polymer Lutrol F 68 Cremophor RH 40 PEG T g [ C] Kollidon VA 64 Soluplus Kollidon 12 PF Kollidon 17 PF Figure T g of pure polymers in comparison to polymer-plasticizer combinations (extrudate, 9:1, w / w %) 180 Pure polymer Lutrol F 68 Cremophor RH 40 PEG 1500 T g [ C] Kollidon 30 (*) Kollidon 90 F (*) Kollidon SR Figure T g of pure polymers in comparison to polymer-plasticizer combinations (extrudate and film (*), 9:1, w / w %), another color in the bar represents the presence of another T g 36

38 It is a well-known fact that the glass transition temperature can be reduced by the addition of plasticizers. However, the additives tested acted in a different way. Whereas PEG 1500 and Cremophor RH 40 decreased the glass transition temperatures in all systems signifi cantly, Lutrol F 68 had no effect on several polymers. From these results, it can be concluded that PEG 1500 and Cremophor RH 40 dissolve more homogeneously in most of the polymers tested than Lutrol F DSC-Analysis of Polymer Mixtures In these experiments, the extrudates of completely molten polymer mixtures were used as samples. If the polymers are completely miscible, only one T g should occur. For an immiscible mixture, two glass transition temperatures (T g signals of polymers) should be found. Similar principles also apply to the melting peaks of the crystalline polymers. Partial miscibility would also result in two glass transition temperatures where at least one is shifted [56]. 3 Table Tested polymer combinations (extrudates) by DSC-analysis Matrix Polymer Kollidon SR Kollicoat IR Kollidon 30 Kollidon 90 F Kollidon VA 64 70:30 70:30 70:30 70:30 30:70 30:70 30:70 - Soluplus 70:30 70:30 70:30 70:30 30:70 30:70 30:70 - Experimental method: Preparation of the polymer mixtures by extrusion (Detailed information, see chapter 3.1.2): Extruder: ZSK 25 (Coperion Werner & Pfl eiderer, Germany) Throughput: 4 5 kg / h Extrusion temperature: C Screw speed: rpm Kollidon VA 64 and Soluplus with Kollidon SR Despite the fact that Kollidon VA 64 and Kollidon SR contain the same monomers but in a different polymer structure, they are obviously not miscible, since all glass transition temperatures remained almost the same. The slight increase of the T g of Kollidon VA 64 can be attributed to a lower water content of the extrudates or a partial mixing of the PVP contained in Kollidon SR with Kollidon VA

39 The DSC curves of the Soluplus Kollidon SR extrudates show a comparatively wide and unsharp peaks. However, partial miscibility is obvious since with 30 % Kollidon SR, no PVP peak with a molecular weight of ~ Dalton can be detected anymore. With larger quantities (70 % Kollidon SR) the typical T g of PVP of approx. 160 C is still visible. Parallel to this, the T g of Soluplus increases Pure polymer Polymer : Kollidon SR, 70:30 Polymer : Kollidon SR, 30:70 Kollidon SR T g [ C] Kollidon VA 64 Soluplus Figure Glass transition temperatures of the pure polymers and combinations of Kollidon VA 64 and Soluplus with Kollidon SR (extrudates) Kollidon VA 64 and Soluplus with Kollicoat IR Kollidon VA 64 and Soluplus in combination with Kollicoat IR are not completely miscible in the tested concentrations, as can be seen from the melting point of Kollicoat IR. The decrease in glass transition temperature of Soluplus and Kollidon VA 64 in combination with Kollicoat IR seems to be affected by the low T g of this compound. 38

40 T g /T m * [ C] * 212* Kollidon VA * 45 Pure polymer Polymer : Kollidon IR, 70:30 Polymer : Kollidon IR, 30:70 Kollicoat IR *melting point * 215* Soluplus 208* 45 3 Figure Glass transition temperatures of the pure polymers and combinations of Kollidon VA 64 and Soluplus with Kollicoat IR (extrudates) Kollidon VA 64 and Soluplus with Kollidon 30 and Kollidon 90 F The extrudates of Kollidon VA 64 and Soluplus with Kollidon 30 and Kollidon 90 F demonstrate that these polymers are not miscible by melting and homogenizing in a hot-melt extrusion process. All experiments with Soluplus and Kollidon VA 64 in combination with PVP have shown that the glass transition temperatures of the used components remain almost unchanged. Slight variations in the glass transition temperature of the polymers can be explained by the different drying method used compared to the experiments with the pure polymers. 39

41 T g [ C] Pure polymer Polymer : Kollidon 30, 70:30 Polymer : Kollidon 30, 30:70 Kollidon Kollidon VA 64 Soluplus Figure Glass transition temperatures of the pure polymers and combinations of Kollidon VA 64 and Soluplus with Kollidon 30 (extrudates) Pure polymer Polymer : Kollidon 90 F, 70:30 Polymer : Kollidon 90 F, 30:70 Kollidon 90 F T g [ C] not extrudable Kollidon VA 64 not extrudable Soluplus Figure Glass transition temperatures of the pure polymers and combinations of Kollidon VA 64 and Soluplus with Kollidon 90 F (extrudates) 3.2 Melt Viscosity Besides the glass transition temperature, the melt viscosity is another crucial factor determining extrudability. 40

42 Experimental method: Viscosity: Viscosity studies were performed using a shear stress-controlled rotational rheometer (SR5 Rheometrics, USA) at three different temperatures with a plate-toplate measuring geometry (diameter of 25 mm, height of 1 mm) Melt Viscosity of Pure Polymers It is worthwhile obtaining these values in order to get some idea about the lowest process temperature to be used for the polymers in the hot-melt extrusion process. The infl uence of shear rate and temperature on the melt viscosity characteristics of the polymers was investigated. 3 Influence of shear rate on melt viscosity All the polymers tested showed a decrease in dynamic melt viscosity with increasing angular frequency and shear rate respectively. Some of the tested polymers showed an unproportional increase in dynamic viscosity at higher temperatures and lower angular frequencies. This might well indicate an initiating cross-linking of the polymer chains. The infl uence of frequency/shear on the melt viscosity of the polymers is displayed for temperatures within the process temperature range of the pure polymers Kollidon VA 64 (170 C) Soluplus (170 C) Kollidon 12 PF (130 C) Kollidon 17 PF (180 C) Kollidon 30 (190 C) Kollidon 90 F (200 C) Kollidon SR (170 C) Kollicoat MAE 100P (150 C) Kollicoat IR (180 C) Kollicoat Protect (180 C) Viscosity* [Pa s] Angular frequency [rad/s] 1000 Figure Melt viscosity of pure polymers as a function of angular frequency 41

43 - Lutrol F127 at 60 C - Lutrol F127 at 70 C - Lutrol F127 at 80 C 100 Viscosity* [Pa s] Angular frequency [rad/s] Figure Melt viscosity of Lutrol F 127 as a function of the angular frequency at different temperatures Influence of temperature on melt viscosity With increasing temperature, the dynamic viscosity of all tested polymers decreased. Only Kollicoat IR showed a slightly higher viscosity at 190 C compared to the viscosity at 180 C. This can probably be explained by an initiating cross-linking of the polymer chains. All the values presented in Figure and were determined at 16 rad / s. Melt viscosity is infl uenced by molecular weight and any interaction between the functional groups of the polymer chains. Thus, signifi cant differences between the various polymers were found. Melt viscosity increased strongly when going from Kollidon 12 PF (~ 2500 Dalton) to Kollidon 17 PF (~ 9000 Dalton), Kollidon 30 (~ Dalton) and Kollidon 90 F ( Dalton). Despite a high molecular weight, Soluplus ( Dalton) results in a similar viscosity to Kollidon VA 64 (~ Dalton). For a small scale extruder, the limitation is at approximately Pa*s since higher viscosities generate too much torque. On the other hand, the polymer should not exhibit a very low viscosity because of problematic downstream processing. 42

44 Kollidon VA 64 Soluplus Kollidon 12 PF Kollidon 17 PF Kollidon 30 Kollidon 90 F Kollidon SR Kollicoat MAE 100P Kollicoat IR Kollicoat Protect Viscosity* [Pa s] Optimal melt viscosity range for HME Temperature [ C] Figure Melt viscosity of pure polymers as a function of temperature Lutrol F Viscosity* [Pa s] Optimal melt viscosity range for HME Temperature [ C] Figure Melt viscosity of Lutrol F 127 as a function of temperature 43

45 3.2.2 Influence of Plasticizers on Melt Viscosity Sometimes melt viscosities have to be lowered in order to be able to run a smoother process. This can be achieved by adding plasticizers. We recommend not using liquid plasticizers but solid or at least semi-solid ones since their diffusivity in the matrix is limited; this leads to better stability. Cremophor RH 40, Lutrol F 68 and PEG 1500 are all effective in reducing viscosity, the most pronounced effect being with Lutrol F 68. All the values presented in Figure were determined at 16 rad / s Kollidon VA 64 Kollidon VA 64 / Lutrol F 68 (4:1) Kollidon VA 64 / Cremophor RH 40 (4:1) Kollidon VA 64 / PEG 1500 (4:1) Viscosity* [Pa s] Temperature [ C] Figure Influence of different plasticizers on the melt viscosity of Kollidon VA 64 44

46 3.3 Decomposition by TGA In principle, all organic materials can be degraded by increasing temperature. Thermal gravimetric analysis (TGA) is a suitable tool for examining the thermal sensitivity of a polymer. At least at the extrusion temperature, which is usually between 100 C and 200 C, it must be stable. Even if this method is not capable of delivering detailed information about cross-linking of the polymer chains and a few other possible reactions, it provides at least an idea about the changes that take place upon heating. Thus, changes in the mass with increasing temperature and the kind of reactions (endothermic or exothermic) can be determined. One more thing which has to be considered, is the time during which the material is exposed to the temperature. Long heat exposure might lead to decomposition, while the material is stable for a shorter time at the same temperature. Exemplarily, a TGA diagram of Soluplus is shown in Figure Experimental method: Thermo gravimetric analyses (TGA): TGA were performed using a Netzsch STA 409 C / CD instrument (USA). TGA scans were recorded at a heating rate of 5 K / min until 450 C (air atmosphere). 100 Mass Change: -2.5% Mass Change: -24.1% 90 Loss of water Start of decomposition Mass [%] Mass Change: -56.1% 20 [1] Temperature/ C Figure TGA diagram example of Soluplus 45

47 3.3.1 TGA of Polymers The difference between glass transition temperatures (T g ) or melting temperature (T m ) and T (degradation) serves as an indication of the extrusion range, which is defi ned as the temperature range within which extrusion can be performed from a process and stability point of view. The broadest range by far was found with Soluplus, followed by Kollidon VA 64, Kollidon 12 PF and Lutrol F 127. Materials with a high T g can only be extruded within a small, relatively high temperature range. 300 T g (or *T m ) T (degradation) Temperature [ C] * * * Kollidon VA 64 Soluplus Kollidon 12 PF Kollidon 17 PF Kollidon 30 Kollidon 90 F Kollidon SR Kollicoat MAE 100P Kollicoat IR* Kollicoat Protect* Lutrol F127* Figure Comparison of T g or T m (by DSC) with T (degradation) (by TGA) of pure polymers TGA of Plasticizers Since plasticizers are often included in formulations for extrusion, they also must be stable at high temperatures. Based on the results obtained, PEG 1500 can be used at up to 175 C, Lutrol F 68 at up to 180 C and Cremophor RH 40 at up to 200 C. 46

48 T m T (degradation) Temperature [ C] White to yellowish paste at 20 C Lutrol F 68 Cremophor RH 40 PEG 1500 Figure Comparison of T m (by DSC) with T (degradation) (by TGA) of pure plasticizers TGA of Active Pharmaceutical Ingredients The TGA results of the three model drugs fenofi brate, carbamazepine and itraconazole indicate that these can be extruded at temperatures up to at least 180 C. Of course, for a detailed investigation, HPLC analysis should be performed. 47

49 T m T (degradation) Temperature [ C] Fenofibrate Carbamazepine Itraconazole Figure Comparison of T m with T (degradation) (by TGA) of active pharmaceutical ingredients 48

50 3.4 Specific Heat Capacity of Pure Polymers The specifi c heat capacity is the amount of heat that must be added (or removed) from a unit mass of a substance to change its temperature by one degree Kelvin. This was determined by DSC-experiments and is helpful in designing the screw confi guration for the extrusion of the polymer. The higher the specifi c heat capacity, the more energy has to be generated and transferred into the polymer to melt it. Principally, such a polymer requires a more aggressive screw confi guration. Experimental method: Differential Scanning Calorimetry (DSC): DSC studies were performed using a Q2000 TA Instrument (USA). DSC scans were recorded at a heating rate of 20 K /min in the second heating run. 3 Table Compilation of the specific heat capacity of the tested polymers at 25.0 C, C and C Sample cp (25.0 C) [J / gk] cp (100.0 C) [J / gk] cp (175.0 C) [J / gk] Kollidon VA Soluplus (145 C) Kollidon 12 PF Kollidon 17 PF Kollidon Kollidon 90 F Kollidon SR Kollicoat MAE 100P (150 C) Kollicoat IR Kollicoat Protect Lutrol F x The polymers tested showed specifi c heat capacities in a range of 1.5 to 2.5 J / gk. The highest values were found for Kollicoat IR and Kollicoat Protect. For processing these polymers more energy has to be transferred in the hot-melt extrusion process. 49

51 c p [J/gK] Kollidon VA 64 Soluplus Kollidon 12 PF Kollidon 17 PF Kollidon 30 Kollidon 90 F Kollidon SR Kollicoat MAE 100P Kollicoat IR Kollicoat Protect Lutrol F127 Figure Compilation of the specific heat capacity (c p ) of the polymers at 100 C 50

52 3.5 API Solubility Enhancement of Pure Polymers A potential affi nity between polymers and a drug that is poorly soluble in water can be pretested using various methods. The solubilization capacity of the different polymers can be tested by determining the saturation solubility of such a poorly soluble drug in a polymer solution. Using phosphate buffer as a solvent (e.g. ph 7.0) ensures comparable conditions when testing ionic solubilizers or drugs. Thus, solubility effects due to ph shifts can be avoided. Experimental method: Solubilization procedure: A 10 % polymer solution in phosphate buffer is oversaturated with a discrete drug and stirred for 72 h at room temperature. The resulting suspension is fi ltered through 0.45 µm fi lter and the content of solubilized drug is determined in the fi ltrate by UV spectroscopy with the 8453 UV-Visible spectrophotometer (Agilent, USA). 3 Active (excess) H 2 O Polymer (10 w%) 72 h stirring, room temperature Filtration UV detection of solubilized active UV Preparation of saturated solution of drug in 10 % polymer solution 72 h stirring (room temperature) and fi ltration (0.45 µm fi lter) Determination of dissolved amount of drug by UV / Vis Figure Solubilization setup The following fi gures show the results of the solubility enhancement of different polymers and PEG 1500 as a plasticizer for various water-insoluble drugs in comparison with the API solubilities in phosphate buffer at ph 7.0. Soluplus outperformed by far all other polymers and resulted in an enhancement of the saturation solubility for all tested drugs. From these results it is obvious that Soluplus is capable of effectively solubilizing these water-insoluble drugs. Higher solubilities were achieved only in the case of piroxicam with other polymers, in particular for Kollidon VA 64; this was caused by a specifi c complexation of this drug with the vinylpyrrolidone and vinyl acetate moiety. In contrast, Soluplus increases drug solubility mainly by forming micelles, which can take up lipophilic drugs almost independently of their structures. 51

53 Saturation solubility [g/100ml] Estradiol ~0.001 Piroxicam ~0.026 * Clotrimazole * ~0.001 Carbamazepine ~0.013 Griseofulvin ~0.080 * Ketoconazole ~0.001 * Cinnarizine Kollidon VA 64 Soluplus Kollidon 17 PF Pure API *No improvement of solubility ~0.001 * Fenofibrate ~ * * Itraconazole ~ * * Danazol ~ Figure Solubility enhancement of Kollidon VA 64, Soluplus and Kollidon 17 PF for various drugs in comparison to the API solubilities in phosphate buffer at ph Kollidon SR Kollicoat IR PEG 1500 Pure API Saturation solubility [g/100ml] Estradiol ~0.001 Piroxicam ~0.026 * ** ~0.001 Clotrimazole Carbamazepine ~0.013 Griseofulvin ~0.080 Ketoconazole ~0.001 * * * ~0.001 Cinnarizine *No improvement of solubility Fenofibrate ~ * * * * Itraconazole ~ Danazol ~ Figure Solubility enhancement of Kollidon SR, Kollicoat IR and PEG 1500 for various drugs in comparison to the API solubilities in phosphate buffer at ph

54 3.6 Calculation of Solubility Parameters of Pure Polymers, Plasticizers and APIs The computer program SPWin (version 2.1) was used for calculation of the threedimensional solubility parameters for polar systems according to Hansen [57]. This program contains an advanced parameter set based on the group contribution methods of Fedors [58] and Van Krevelen and Hoftyzer [59]. Group contribution by Fedors and Van Krevelen and Hoftyzer were combined by Braun and Gröning [60] and were modifi ed and optimized by Breitkreutz for the software SPWin 2.1. For the calculation the structures of the polymers, plasticizers and drugs have to be divided into functional groups, whereby each atom may only occur once. The determining factor for the affi liation to a group is its priority in chemical nomenclature. The solubility parameters of polymers and plasticizers are always related to an approximate molecular weight given in chapter 2 General Notes on BASF Pharma Polymers. The number of groups can be determined from the molecular weight of the polymer or plasticizer and the structure of the monomer. For Cremophor RH 40 containing different structures, the calculation of the solubility parameter did not make much sense [61]. 3 Solubility parameters were defined as: δ d dispersion components Components of intermolecular dispersion or Van der Waals forces δ d = F di i V i i i F d V i Structural group within the molecule Group contributions to dispersion forces Group contributions to molar volume δ p polar components Components of intermolecular polar forces δ p = 2 F pi i V i i i F p V i δ h hydrogen bonding components Components of intermolecular hydrogen bonding Structural group within the molecule Group contributions to polar forces Group contributions to molar volume δ h = E hi i V i i i E h V i Structural group within the molecule Group contributions to hydrogen bond energy Group contributions to molar volume 53

55 δ v calculation of the combined solubility parameters δ d and δ p δ v = 2 2 δ d + δ p δ total calculation of the combined solubility parameters δ d, δ p and δ h δ total = δ d + δ p + δ h The calculated solubility parameter can be used as an initial tool to predict the miscibility of compounds. Agents with similar δ values are expected to be miscible. The polymers and plasticizers show quite similar δ d, δ p, δ h,δ v and (δ total ) solubility parameters (except Kollicoat IR). The parameters for the APIs display compliance between fenofi brate and itraconazole and a higher deviation for carbamazepine. Table Three-dimensional (δ d, δ p, δ h ), combined (δ v ) and total (δ total ) solubility parameters of different polymers Polymer δ d [MPa 0.5 ] δ p [MPa 0.5 ] δ h [MPa 0.5 ] δ v [MPa 0.5 ] δ total [MPa 0.5 ] Kollidon VA Soluplus Kollidon 12 PF Kollidon 17 PF Kollidon Kollidon 90 F Kollidon SR Kollicoat MAE 100P* Kollicoat IR Kollicoat Protect Lutrol F * Calculated for the acid form 54

56 Table Three-dimensional (δ d, δ p, δ h ), combined (δ v ) and total (δ total ) solubility parameters of different plasticizers Plasticizer δ d [MPa 0.5 ] δ p [MPa 0.5 ] δ h [MPa 0.5 ] δ v [MPa 0.5 ] δ total [MPa 0.5 ] Lutrol F PEG Table Three-dimensional (δ d, δ p, δ h ), combined (δ v ) and total (δ total ) solubility parameters of different APIs 3 API δ d [MPa 0.5 ] δ p [MPa 0.5 ] δ h [MPa 0.5 ] δ v [MPa 0.5 ] δ total [MPa 0.5 ] Fenofibrate Carbamazepine Itraconazole

57 4 Design of Extrusion Experiments The hot-melt extrusion technique was used to process BASF pharma polymers in the absence and presence of different plasticizers. Moreover, different blends were also produced using combinations of some of these polymers. This chapter mainly provides detailed information on the hot-melt extrusion set up, experimental procedure, processing conditions, effect of plasticizers on processing of the polymers and handling of the extruded products. 4.1 Extrusion of Pure Polymers The following pure BASF pharma polymers were investigated: Kollidon VA 64 Soluplus Kollidon 12 PF Kollidon 17 PF Kollidon 30 Kollidon 90 F Kollidon SR Kollicoat MAE 100P Kollicoat IR Kollicoat Protect Lutrol F Extrusion Temperature Range of Pure Polymers The polymers were processed at different temperatures in a co-rotating twin-screw extruder. The temperature range selected was the lowest possible processing temperature to the highest. The lowest temperature was determined by various factors such as T g or T m, the melt viscosity, the power consumption of the twin-screw extruders (by means of Ampere) and the pressure in the extruder. The highest possible processing temperature was determined by the thermal stability of the polymers. Experimental method: Extrusion (for more detailed information, see chapter 3.1.2): Extruder: ZSK 25 (Coperion Werner & Pfl eiderer, Germany) Throughput: 2 to 5 kg / h Extrusion temperature: C Screw speed: rpm 56

58 Taking the T g or T m (by DSC), the melt viscosity and the T (degradation) (indicated by start of mass reduction by TGA or discoloration) and the determination of the lowest and highest processing temperatures by hot-melt extrusion into consideration, Kollidon VA 64, Soluplus, Kollidon 12 PF and Lutrol F 127 demonstrated excellent suitability for extrusion. Kollidon 17 PF, Kollidon SR, Kollicoat IR and Kollicoat Protect were diffi cult to extrude because of a higher T g or T m, melt viscosities and the smaller difference of T (degradation) to T g. Povidones of higher molecular weight (Kollidon 30 and Kollidon 90 F) and Kollicoat MAE 100P as pure polymers were not processed by HME due to their degradation. Temperature [ C] Kollidon VA 64 4 Kollidon 12 PF Soluplus Kollidon 17 PF Lutrol F 127 above 60 C low viscous liquids Kollidon SR Kollicoat IR Kollicoat Protect Figure Temperature ranges for the extrusion of pure polymers 57

59 4.1.2 Appearance and Pelletizing Characteristics of Extrudates Appearance and pelletizing behavior of the extrudates are important characteristics from the product and process point of view. Appearance of Kollidon VA 64 The extrudates of Kollidon VA 64 look quite clear, glassy and regular. With increasing extrusion temperature the color turns yellowish and brownish. Above 220 C extrusion temperature, pelletizing under the set extrusion conditions becomes quite diffi cult. 160 C 180 C 220 C 240 C Figure Extrudate of Kollidon VA 64 Appearance of Soluplus Soluplus also appears clear, glassy and regular as an extrudate at low temperatures. Above 200 C, the color changes slowly into yellowish / golden. 160 C 180 C 200 C 220 C Figure Extrudate of Soluplus 58

60 Appearance of Kollidon 12 PF The extrudates of Kollidon 12 PF are quite clear and brittle; this leads to a wide particle size distribution and irregular shapes. 100 C 130 C 150 C Figure Extrudate of Kollidon 12 PF C Appearance of Kollidon 17 PF The extrudate of Kollidon 17 PF appears quite clear and brittle; this leads to a wide particle size distribution and irregular shapes. Figure Extrudate of Kollidon 17 PF Appearance of Kollidon SR Extrudates of Kollidon SR are yellowish opaque. Kollidon SR remains fl exible for a comparatively long time (after leaving the extruder). For this reason, pelletizing of the strands of pure polymer is challenging. 170 C 180 C 200 C Figure Extrudate of Kollidon SR 59

61 160 C Appearance of Kollicoat IR The extrudate of Kollicoat IR looks quite clear and regular. With increasing extrusion temperature, the color becomes slightly darker. However, Kollicoat IR extrudates processed at temperatures of 160 C are no longer completely water-soluble. Figure Extrudate of Kollicoat IR 160 C Appearance of Kollicoat Protect The extrudate appears quite clear to cloudy and regular. With increasing extrusion temperature, the color becomes slightly darker. However, Kollicoat Protect extrudates processed at temperatures of 160 C are no longer completely water-soluble. Figure Extrudate of Kollicoat Protect Appearance of Lutrol F 127 Lutrol F 127 melts at a comparatively low temperature and shows an extremely low viscosity already around 60 C, so that cooling and pelletizing is a challenge. The extrudate of Lutrol F 127 is white. 60 C 100 C 200 C Figure Extrudate of Lutrol F

62 Table Overview of the appearance and pelletizing behavior of pure polymer extrudates + Good pelletizing behavior o Poor pelletizing behavior - Pelletizing is impossible Polymer Processing Temperature [ C] Characteristics Pure Polymer Kollidon VA Appearance: Clear Pelletizing: + (Regular pellets) Soluplus 120 Appearance: Clear Pelletizing: + (Regular pellets) Kollidon 12 PF 100 Appearance: Quite clear Pelletizing: + (Irregular pellets, brittle extrudates) Kollidon 17 PF 175 Appearance: Quite clear Pelletizing: o (Brittle extrudate) Kollidon SR 135 Appearance: Opaque, slight yellowish Pelletizing: + (Regular pellets) Kollicoat IR 160 Appearance: Quite clear Pelletizing: + (Regular pellets) Kollicoat Protect 160 Appearance: Quite clear to cloudy Pelletizing: + (Regular pellets) Lutrol F Appearance: White Pelletizing: - (> 60 C low viscose liquid) 4 Soluplus and Kollidon VA 64 extrudates have a clear appearance and show good pelletizing behavior. Fairly good results for pelletizing were achieved with Kollicoat IR, Kollicoat Protect and Kollidon SR. Within the range of PVP polymers, Kollidon 12 PF demonstrated better pelletizing behavior than Kollidon 17 PF although both polymers have a tendency to create brittle extrudates. The pelletizing of Lutrol F 127 was impossible because of the low viscosity of the extrudate at 60 C. 61

63 4.1.3 Dissolution Characteristics of Polymer Extrudates In order to determine the dissolution characteristics of the extrudates, dissolution experiments in different media were performed. Experimental method: Dissolution: These were conducted in a USP-conform dissolution apparatus with 900 ml volume at 100 rpm. The cylindrical extrudates of approximately 2 cm length and a diameter of 4 mm were tested in several buffer media with different ph-values (1.1, 6.8 and 9.0). Table Dissolution time of tested extrudates in a USP-conform dissolution apparatus Extrusion Sample temperature Dissolution time [h:min] [ C] ph-value 1.1 ph-value 6.8 ph-value 9.0 Kollidon VA :17 00:21 00:19 Soluplus :15 01:35 01:43 Kollidon 12 PF :04 00:06 00:08 Kollidon 17 PF :08 00:06 00:09 Kollidon SR 180 >24:00 >24:00 >24:00 Kollicoat IR 160 >24:00 >24:00 >24:00 Kollicoat Protect 160 >24:00 >24:00 >24:00 Lutrol F :01 00:30 01:12 Kollidon VA 64, Soluplus, Kollidon 12 PF, Kollidon 17 PF and Lutrol F 127 dissolved completely in aqueous media of various ph within a short period of time. As expected, Kollidon SR extrudates did not dissolve since they contained polyvinyl acetate as a water-insoluble polymer. Surprisingly, Kollicoat IR and Kollicoat Protect, as water-soluble polymers, also did not dissolve completely. This effect might be a result of a cross-linking reaction caused by the high extrusion temperatures. Other experiments with Kollicoat IR in combination with plasticizer and at lower extrusion temperature showed complete dissolution in aqueous media. 62

64 4.1.4 Decomposition of Polymers during Extrusion In addition to TGA analysis, GPC (Gel Permeation Chromatography) of Kollidon VA 64 and Soluplus was performed. The GPC was conducted in order to capture crosslinking or split of the polymer chains. Additionally, chemical test parameters according to the Certifi cate of Analysis were performed to study the stability of Kollidon VA 64 and Soluplus in the hot-melt extrusion process. Kollidon VA 64 As the curves show, there was no change in molecular weight distribution after extrusion at 160 C. Furthermore, the chemical parameters reveal no signifi cant difference; in particular no saponifi cation of the ester group could be determined. Backsplit of the polymer chain into monomers was also not observed. 4 Kollidon VA 64 LOT L0 extruded 160 C Kollidon VA 64 LOT L w(log(m)) ,000 10, ,000 M/Da 1,000,000 10,000,000 Figure Molecular weight distribution curves of Kollidon VA 64 (powder) and Kollidon VA 64 (extrudate) 63

65 Test parameter Requirements Results powder Results extrudate Vinyl acetate Vinyl pyrrolidone Acetaldehyde Peroxide [mg / kg] [mg / kg] [mg / kg] [mg / kg] max. 10 <10 <10 max. 10 <2 <2 max. 500 <10 <10 max. 400 <20 <20 2-Pyrrolidone [g / 100g] Saponifi cation value [mg KOH / g] 0, ph-value (10 % in solution) min. 3.0 max K-value (1 % aqueous solution) min max Figure Stability of Kollidon VA 64 during extrusion at 160 C Soluplus Comparable to Kollidon VA 64, Soluplus also showed no degradation. The molecular weight remained constant, as did the chemical parameters. A split of the ester or the caprolactam from the polymer chain would have led to lower ester and ph-values, higher acetic acid values and higher caprolactam concentrations. 64

66 Test parameter Powder Extrudate [extruded at 140 C] Extrudate [extruded at 180 C] Identifi cation (IR) ph-value Ester value [mg KOH / g] conforms conforms conforms Vinyl acetate Vinyl caprolactam [ppm] [ppm] <2 <2 <2 <10 <10 <10 Caprolactam [g / 100g] Ethylenglykole Acetic acid / Acetate [ppm] [ppm] < Peroxide [ppm] <20 <20 <20 Molecular weight Mw [g / mol] 118, , ,000 No change in chemical and physico-chemical parameters up to 180 C Figure Stability of Soluplus during extrusion at 140 C and 180 C 65

67 4.2 Extrusion of Polymer-Plasticizer Combinations The specifi c objective was to investigate the effect of various plasticizers on the processing temperature of different polymers. Polymers: Plasticizers: Kollidon VA 64 Lutrol F 68 Soluplus Cremophor RH 40 Kollidon 12 PF PEG 1500 Kollidon 17 PF Kollidon SR Kollicoat IR Kollicoat Protect Extrusion Temperature Range of Polymer-Plasticizer Combinations Three plasticizers Lutrol F 68, Cremophor RH 40 and PEG 1500 were investigated. In general, it was found that 10 % (w / w) of the plasticizers were suffi cient for a signifi cant decrease in extrusion temperatures. Lutrol F 68 and PEG 1500 could be added in powder form using a separate powder feeder. Cremophor RH 40 was added in molten form using a melt pump. The temperature range for extrusion was determined according to the method employed for the pure polymers. Experimental method: Extrusion (for more detailed information, see chapter 3.1.2): Extruder: ZSK 25 (Coperion Werner & Pfl eiderer, Germany) Throughput: 2.5 to 5 kg / h Extrusion temperature: C Screw speed: rpm It is obvious that all the polymer-plasticizer combinations could be processed below the processing temperatures of the pure polymers; however, this reduction was not the same for all the polymers. The highest reduction of 50 C was observed for Kollidon SR with all three plasticizers. This is in line with previous studies on the plasticizing effects in fi lm coatings based on polyvinyl acetate, where small amounts also showed a tremendous effect. The type of plasticizer also had a signifi cant impact since PEG 1500 decreased the extrusion temperatures more than the others. This can probably be attributed to the low molecular weight of this plasticizer. 66

68 Pure Polymer + 10% Lutrol F Temperature [ C] Kollidon VA 64 Soluplus Kollidon 12 PF Kollidon 17 PF Kollidon SR No effect of plasticizer * No effect of plasticizer * Kollicoat IR Kollicoat Protect 4 Figure Temperature range for extrusion of polymer / Lutrol F 68 combinations (9:1, w / w %) Pure Polymer Temperature [ C] + 10% Cremophor RH Kollidon VA 64 Soluplus Kollidon 12 PF Kollidon 17 PF Kollidon SR No effect of plasticizer * No effect of plasticizer * Kollicoat IR Kollicoat Protect Figure Temperature range for extrusion of polymer / Cremophor RH 40 combinations (9:1, w / w %) 67

69 Pure Polymer Temperature [ C] + 10% PEG Kollidon 12 PF Soluplus Kollidon SR Kollidon VA 64 Kollicoat IR Kollicoat Protect Kollidon 17 PF Figure Temperature range for extrusion of polymer / PEG 1500 combinations (9:1, w / w %) Appearance and Pelletizing Characteristics of Polymer-Plasticizer Extrudates The appearance of the polymer-plasticizer extrudates and pelletizing behavior are important characteristics, particularly for downstream processing. The type of plasticizer had a signifi cant impact since PEG 1500 only slightly deteriorated the appearance and pelletizing behavior of the polymer-plasticizer extrudates compared to the extrudates of pure polymer. More deviation of appearance and pelletizing was observed for Lutrol F 68, the strongest deviation being observed for Cremophor RH 40. In general, the addition of plasticizers made pelletizing more diffi cult. Quite often, appearance changed from clear to opaque. 68

70 Table Overview of appearance and pelletizing behavior of different extrudates in the presence of plasticizers (ratio polymer to plasticizer 9:1, w / w %) + Good pelletizing behavior o Poor pelletizing behavior Polymer Kollidon VA 64 Soluplus Kollidon 12 PF Kollidon 17 PF Kollidon SR Kollicoat IR Kollicoat Protect Plasticizer 10 % (w / w %) Characteristics Cremophor Lutrol F 68 PEG 1500 RH 40 Appearance: Opaque Opaque Clear Pelletizing: + (150 C) (Irregular pellets) + (150 C) (Irregular pellets) + (150 C) (Irregular pellets) Pelletizing: o (135 C) o (125 C) o (125 C) Appearance: Clear Clear Clear + (120 C) o (120 C) o (120 C) (Regular pellets) o (100 C) o (100 C) + (90 C) (Irregular pellets) Appearance: Opaque Opaque Almost clear Pelletizing: o ( C) o ( C) o ( C) Appearance: Opaque Opaque Clear Pelletizing: Appearance: Pelletizing: o ( C) (Brittle extrudate) Opaque (Yellowish) + (135 C) (Regular pellets) o ( C) (Brittle extrudate) Opaque (Yellowish) o (135 C) o ( C) (Brittle extrudate) Opaque (Yellowish) + (135 C) (Regular pellets, stick together) o (85 C) o (85 C) o (85 C) Appearance: Opaque Opaque Almost clear Pelletizing: o (160 C) o (160 C) + (140 C) (Irregular pellets) Appearance: Opaque Opaque Almost clear Pelletizing: + ( C) (Irregular pellets) o ( C) + (180 C) (Irregular pellets) o (170 C) 4 69

71 4.2.3 Miscibility of Polymer-Plasticizer Combinations The miscibility of the polymers used in combination with the plasticizers (polymerplasticizer combinations of 9:1, w / w %) was determined by visual inspection of the mixtures and by determination of the T g s and T m s by DSC analysis. A homogeneously clear sample is expected to represent completely miscible combinations. In these experiments, the mixtures were produced using two different experimental methods. Polymer: Plasticizer: Kollidon VA 64 Lutrol F 68 Soluplus Cremophor RH 40 Kollidon 12 PF PEG 1500 Kollidon 17 PF Kollidon 30 Kollidon 90 F Kollidon SR Kollicoat MAE 100P Kollicoat IR Kollicoat Protect Lutrol F 127 Experimental method: 1. Extrusion (for more detailed information, see chapter 3.1.2): Extruder: ZSK 25 (Coperion Werner & Pfl eiderer, Germany) Throughput: 2.5 to 5 kg / h Extrusion temperature: C Screw speed: rpm 2. Polymer-plasticizer films (film casting): A polymer and a plasticizer were dissolved in an appropriate solvent. The solution was cast by Coatmaster (Erichsen Testing Equipment, Germany); the knife had different die gaps ( µm) and the solvent was evaporated until a uniform fi lm remained. Solvent Polymer Solution Film Casting Plasticizer Figure Chart of sample production using the film casting method 70

72 3. Differential Scanning Calorimetry (DSC): DSC studies were performed using a Q2000 (TA Instruments, USA). DSC scans were recorded at a heating rate of 20 K / min during the second heating run. Table Appearance of polymer-plasticizer combinations tested by film casting experiments / hot-melt extrusion and evaluated by visual inspection Clear sample Almost clear sample Opaque sample - Not extrudable * Not relevant because of low melting point Polymer Lutrol F 68 Cremophor RH 40 PEG 1500 Film Film Film Extrudate Extrudate Extrudate Kollidon VA 64 9:1 9:1 9:1 9:1 9:1 9:1 Soluplus 9:1 9:1 9:1 9:1 9:1 9:1 Kollidon 12 PF 9:1 9:1 9:1 9:1 9:1 9:1 Kollidon 17 PF 9:1 9:1 9:1 9:1 9:1 9:1 Kollidon 30 9:1-9:1-9:1 - Kollidon 90 F 9:1-9:1-9:1 - Kollidon SR 9:1 9:1 9:1 9:1 9:1 9:1 Kollicoat MAE 100P 9:1-9:1-9:1 - Kollicoat IR 9:1 9:1 9:1 9:1 9:1 9:1 Kollicoat Protect 9:1 9:1 9:1 9:1 9:1 9:1 Lutrol F127 9:1 * 9:1 * 9:1 * 4 71

73 The extrudates of Kollidon VA 64 in combination with Lutrol F 68 and Cremophor RH 40 were opaque, while the extrudate obtained using PEG 1500 was transparent. Based on the DSC results (Figures to ) and visual inspection, it can be concluded that PEG 1500, in contrast to the others, form a single-phase mixture when melt-extruded with Kollidon VA 64. This is because, in DSC, no melting point for PEG 1500 was found but rather a shift in the T g of Kollidon VA 64. In the case of Lutrol F 68 and Cremophor RH 40, melting points could still be detected, showing that these components could not be incorporated homogeneously and completely. Visual inspection of fi lms can be employed as a good indicator for miscibility of components. 8 Kollidon VA 64 Lutrol F 68 Kollidon VA 64 / Lutrol F 68 6 Heat Flow [W/g] 4 2 Extrudate: Kollidon VA 64 / Lutrol F Temperature [ C] Figure DSC plots of Kollidon VA 64, pure Lutrol F 68 and the Kollidon VA 64 / Lutrol F 68 combination (extrudate, 9:1, w / w %) 72

74 3 2 Kollidon VA 64 Cremophor RH 40 Kollidon VA 64 / Cremophor RH 40 Heat Flow [W/g] 1 Extrudate: Kollidon VA 64 / Cremophor RH Temperature [ C] Figure DSC plots of Kollidon VA 64, pure Cremophor RH 40 and the Kollidon VA 64 / Cremophor RH 40 combination (extrudate, 9:1, w / w %) 10 8 Kollidon VA 64 PEG 1500 Kollidon VA 64 / PEG 1500 Heat Flow [W/g] Extrudate: Kollidon VA 64 / PEG Temperature [ C] Figure DSC plots of Kollidon VA 64, pure PEG 1500 and the Kollidon VA 64 / PEG 1500 combination (extrudate, 9:1, w / w %) 73

75 4.3 Extrusion of Polymer Mixtures Kollidon VA 64 and Soluplus were selected as two different matrix polymers which were then combined with Kollidon SR, Kollicoat IR, Kollidon 30 and Kollidon 90 F to produce different blends Extrusion Temperature Range of Polymer Mixtures The polymer ratios were varied from 100:0 to 0:100 (w / w %) in order to investigate the effect of polymer composition on the minimum processing temperature by extrusion. Table Tested polymer combinations by hot-melt extrusion Polymer Kollidon SR Kollicoat IR Kollidon 30 Kollidon 90 F Kollidon VA 64 70:30 70:30 70:30 70:30 50:50 50:50 50:50-30:70 30:70 30:70 - Soluplus 70:30 70:30 70:30 70:30 50:50 50:50 50:50-30:70 30:70 30:70 - Experimental method: Extrusion (for more detailed information, see chapter 3.1.2): Extruder: ZSK 25 (Coperion Werner & Pfl eiderer, Germany) Throughput: 4 to 5 kg / h Extrusion temperature: C Screw speed: rpm In the case of Kollidon SR, almost no effect of Kollidon VA 64 on the processing temperature was observed. For all compositions with Kollicoat IR, it was possible to process the blends at 150 C. It proved impossible to extrude pure polymers Kollidon 30 and Kollidon 90 F due to their high T g and melt viscosities. In the presence of Kollidon VA 64, Kollidon 30 could be melt processed successfully. Moreover, relatively low processing temperatures were required with an increasing amount of Kollidon VA 64. For Kollidon 90 F, processing of the mixture was possible only with 70 % (w / w) of Kollidon VA 64. However, the appearance of the extrudates of this blend was inhomogeneous. 74

76 The blends of Soluplus with Kollidon SR could be processed at 135 C. For all compositions with Kollicoat IR, the processing temperature could be reduced with increasing amounts of Soluplus. Also, in the presence of Soluplus, Kollidon 30 could be melt-extruded successfully at relatively low processing temperatures by increasing the Soluplus concentration. The combination of Soluplus with Kollidon 90 F behaved similarly to the combination of Kollidon VA 64 with Kollidon 90 F but at slightly lower processing temperatures. The blends were also inhomogeneous because of the high molecular weight of Kollidon 90 F. Pure polymer Polymer : Kollidon SR, 70:30 Polymer : Kollidon SR, 50:50 Polymer : Kollidon SR, 30:70 Kollidon SR T processing [ C] Kollidon VA 64 Soluplus Figure Minimum processing temperature of polymer blends Kollidon VA 64 and Soluplus with Kollidon SR 75

77 T processing [ C] Kollidon VA Pure polymer Polymer : Kollicoat IR, 70:30 Polymer : Kollicoat IR, 50:50 Polymer : Kollicoat IR, 30:70 Kollicoat IR Soluplus Figure Minimum processing temperature of polymer blends Kollidon VA 64 and Soluplus with Kollicoat IR 240 Pure polymer Polymer : Kollidon 30, 70:30 Polymer : Kollidon 30, 50:50 Polymer : Kollidon 30, 30:70 T processing [ C] Kollidon VA 64 Soluplus Figure Minimum processing temperature of polymer blends Kollidon VA 64 and Soluplus with Kollidon 30 76

78 Pure polymer Polymer : Kollidon 90 F, 70: T processing [ C] Kollidon VA 64 Soluplus Figure Minimum processing temperature of polymer blends Kollidon VA 64 and Soluplus with Kollidon 90 F 77

79 4.3.2 Appearance and Pelletizing Characteristics of Extrudates of Polymer Mixtures The appearance of the extrudates and pelletizing behavior of the polymer mixtures are important characteristics, particularly for downstream processing. The two different matrix polymers Kollidon VA 64 and Soluplus in combination with Kollidon SR, Kollicoat IR, Kollidon 30 and Kollidon 90 F showed good pelletizing behavior. The appearance of the extrudates of these blends was opaque and displayed the inhomogeneous nature of the systems. Table Overview of appearance (A) and pelletizing (P) behavior of polymer mixtures Kollidon SR Kollicoat IR P A P A Kollidon VA : :0 + 70: : : : : :70 + 0: :100 Soluplus + 100: :0 + 70: : : : : :70 + 0: :100 Kollidon 30 Kollidon 90 F P A P A Kollidon VA : :0 + 70: : :50 Not processable! o 30:70 Not processable! 30:70 Not processable! 0:100 Not processable! 0:100 Soluplus + 100: :0 + 70: : :50 Not processable! o 30:70 Not processable! 30:70 Not processable! 0:100 Not processable! 0:100 Clear sample Almost clear sample Opaque sample + Good pelletizing behavior o Poor pelletizing behavior 78

80 4.4 Solubilization Capacity of Active Ingredients in Polymers for Hot-Melt Extrusion The solubilization capacity of active pharmaceutical ingredients in solid solutions of the following polymers was investigated. Kollidon VA 64 Kollidon 30 with 10 % PEG 1500 (w/ w %) Soluplus Kollidon 90 F with 20 % PEG 1500 (w/ w %) Kollidon 12 PF Kollicoat MAE 100 P with 10 % PEG 1500 (w/ w %) Kollidon 17 PF Kollicoat IR with 10 % PEG 1500 (w/ w %) Kollidon SR Kollicoat Protect with 10 % PEG 1500 (w/ w %) Lutrol F 127 The APIs fenofi brate, carbamazepine and itraconazole were used as model drugs because of their low solubility. Some polymers had to be combined with % (w / w) PEG 1500 in order to enable extrusion processing at appropriate temperatures. 4 O CH 3 Cl C O C CO O CH(CH 3 ) 2 Fenofibrate (antihypertensive) ~ g / 100 ml in phosphate buffer ph 7.0 CH 3 N CO NH 2 N N N O Cl H O O Cl Carbamazepine (antiepileptic) ~0.013 g / 100 ml in phosphate buffer ph 7.0 N N N O N N CH C 2 H 5 CH 3 Figure Model drugs Itraconazole (fungicide) ~ g / 100 ml in phosphate buffer ph 7.0 The solubilization capacity of the APIs in the solid solutions of the polymers was determined using the two different methods of fi lm casting and hot-melt extrusion. 79

81 4.4.1 Film Casting Solubilization capacity was determined by fi lm casting experiments using fenofi brate, carbamazepine and itraconazole as model drugs in combination with the polymers or polymer-plasticizer combinations described below. Experimental method: Film casting: An appropriate solvent that dissolves the API, the polymer and the plasticizer should be selected. When the substances are dissolved after stirring, the solution can be cast on a glass plate, resulting in a thin fi lm. A scraper that produces a fi lm of 120 µm thickness is recommended as casting device. The thin fi lm (thickness of the dry fi lm <120 µm) enables fast drying and avoids the recrystallization of the poorly soluble drug that can occur when high drug concentrations are used over a longer period, as happens in case of thick fi lms. Drying should be performed for 30 minutes under ambient conditions (fl ue) and then in a vacuum drying cabinet (50 C, 10 mbar for 30 minutes) to ensure fast and complete drying of the fi lm. To analyze the extent of solubilization capacity of the polymer or of the polymer-plasticizer combination for a specifi c drug, increasing amounts of API should be applied for the fi lm casting method (25, 33 and 50 %). The higher the clearly dissolved drug concentration, the higher the solubilization capacity. A solid solution results in clear and smooth fi lms. Drug crystals can easily be recognized as can amorphous precipitation (opaque fi lms). Visual inspection of the fi lms was performed 7 days after open storage at 23 C / 54 % r. h. Solvent Active Polymer or Polymer/plasticizer combinations Blank sample Crystalline sample Preparation of fi lms with 25 %, 33 % and 50 % drug content Observation of fi lm stability drug must not re-crystallize Dried polymer film Figure Film casting procedure 80

82 Soluplus showed the highest solubilization capacity followed by Kollidon VA 64 and Kollidon SR. Kollidons of the lower molecular weight such as Kollidon 12 PF and Kollidon 17 PF dissolved only smaller amounts. For the systems comprising Kollicoat MAE 100P, Kollicoat IR and Kollicoat Protect in combination with itraconazole, no appropriate solvent could be found that dissolved all components. Table Solubilization capacity of fenofibrate, carbamazepine and itraconazole in polymers or polymer-plasticizer combinations High solubility of API Good solubility of API Low solubility of API n. d. Not detected Polymer Drug content [% dissolved in polymer] Fenofibrate Carbamazepine Itraconazole Kollidon VA >50 Soluplus >50 Kollidon 12 PF Kollidon 17 PF < Kollidon 30 * <25 <25 >50 Kollidon 90 F ** <25 <25 >50 Kollidon SR >50 Kollicoat MAE 100P * <25 >50 n. d. Kollicoat IR * <25 <25 n. d. Kollicoat Protect * <25 <25 n. d. Lutrol F 127 <25 <25 <25 * With 10 % PEG 1500 ** With 20 % PEG

83 4.4.2 Extrusion Besides the fi lm experiments, solubilization capacity was also determined using hotmelt extrusion of carbamazepine and itraconazole as model drugs in combination with the following polymers and polymer-plasticizer combinations: Kollidon VA 64 Kollidon 30 with 10 % PEG 1500 (w/ w %) Soluplus Kollidon 90 F with 20 % PEG 1500 (w/ w %) Kollidon 12 PF Kollicoat MAE 100P with 10 % PEG 1500 (w/ w %) Kollidon 17 PF Kollicoat IR with 10 % PEG 1500 (w/ w %) Kollidon SR Kollicoat Protect with 10 % PEG 1500 (w/ w %) Lutrol F 127 Drug content in the extrudates was increased from 10 % to 50 % (w / w) in 5 % steps. All extrudates were investigated by X-ray Diffraction (XRD) or DSC in order to determine the physical state of the incorporated drug. Since stability of solid dispersions can be a critical point, the extrudates were stored in open glass bottles at 25 C / 60 % r.h. for 3 months and tested for physico-chemical changes. In addition dissolution studies were also performed. Increasing drug concentration (w / w %) 25 % 30 % 35 % 40 % 45 % 50 % Figure Appearance of extrudates with increasing drug concentration Experimental method: 1. Extrusion: Melt extrusion was performed using a twin-screw extruder PolyLab OS (ThermoFisher, Germany) with a screw diameter of 16 mm and a length to diameter ratio of 40D. Several extrusion parameters were varied such as the loading of the extruder (from 0.3 to 0.8 kg / h), extrusion temperature ( C) and the speed of the extruder screws (from 50 to 250 rpm). The active ingredient was fed to the 82

84 extruder via a separate feeder, since this allows a simple and quick change of the active concentration in the extrudate. After extrusion, the samples were cooled down on a conveyor belt and subsequently pelletized. Extruder Equipment:: 16 mm screw diameter Different screw elements Variable length of 25 or 40D Gravimetric dosing system Volumetric dosing system Gear pump Belt conveyor Pelletizing device Figure ThermoFisher Extruder PolyLab OS and the extruder equipment used in the trials 4 2. X-ray Diffraction (XRD): XRD studies were performed by using a diffractometer D 8 Advance (Bruker / AXS, Germany). 3. Differential Scanning Calorimetry (DSC): DSC studies were performed using a Q2000 (TA Instruments, USA). DSC scans were recorded at a heating rate of 20 K / min during the fi rst heating run Amorphous system Crystalline system Itraconazole Lin (Counts) Theta-Scale Figure XRD examples of extrudates of Kollidon VA 64 with itraconazole and the pure API itraconazole 83